FDAcGMP检查-hora.ppt

FDAcGMPInspectionsPekingUniversity2005 RobertC Horan PhDFDAPharmaceuticalInspectorateNewYorkDistrict FDAInspections Periodic biennial comprehensivecGMPPre ApprovalInspection PAI Forcause Inspectionmayinvolvemorethanoneassignmentandwillverifycorrectionstopreviousinspections AllinspectionscoverGMPs ForeignInspectionsbyCountryinFY2004 ForeignInspectioninFY2004byFirmType FDAcGMPsfor21stCenturyInitiative Announced8 2002 objectivesinclude EncourageadoptionofnewtechnologiesPromoteindustryuseofmodernqualitysystemapproachesEncouragerisk basedapproacheswhichfocusoncriticalelementsEnsureFDAreview complianceandinspectionpoliciesbasedonstate of artpharmaceuticalscience FDAcGMPsfor21stCenturyInitiative SystemsBasedInspectionsRisk BasedApproachtoManufacturingandRegulationPharmaceuticalInspectoratePATGuidancedocument PATTeamQualitySystemsGuidancedocumentProcessValidation CompliancePolicyGuiderevised Guidancebeingrevised 21CFRPart11ElectronicRecordsGuidance risk based gearedtowardGMPdocuments PharmaceuticalInspectorate CadreofmostexperiencedinvestigatorswhoarededicatedtodruginspectionsIntensivelytrainedalongwithqualityreviewersandcompliancestaffinFDAheadquarters HQ OverallgoalistohavePIworkcloselywithHQpersonnel moreefficientlyintegratereviewandinspectionfunctions PharmaceuticalInspectorate FDAReviewstaff ComplianceOfficersandPIcandidatesattendedtrainingmoduleswhichfocusedon CurrentRegulatoryProgramsAdvancedQualitySystemsPATandModernPharmaceuticalTechnologyRiskManagement PharmaceuticalInspectorate FieldInvestigators 18 fromacrossU S makeupthePharmaceuticalInspectorateScreeningprocesswithcertificationboardCompletedtrainingwithHQpersonnelOnemonthdetailworkingwithHQstaffLevelIIIcertification highestlevel ConductPAIs complexdruginspections ProcessAnalyticalTechnology PATisasystemfordesigning analyzingandcontrollingmanufacturingthrough realtime measurementsofcriticalqualityattributesofrawandin processmaterialsandprocesses withthegoalofensuringfinalproductquality SeeFDAGuidancedocumentonPAT ProcessAnalyticalTechnology ExamplesofPATapplications Continuousrealtimemeasurementsofcontentuniformityoftabletsduringproduction usingnearInfra Red NearIRmeasurementofmoisturelevelduringAPIdryingprocesstodetermineactualendofoperationforeachbatch ProcessAnalyticalTechnology Aprocessisgenerallyconsideredwellunderstoodwhen AllcriticalsourcesofvariabilityareidentifiedandexplainedVariabilityismanagedbytheprocess Qualitycannotbetestedintoproducts itshouldbebuilt inorshouldbebydesign ProcessValidation LifeCycleApproachProcessvalidationbeginswithprocessdevelopmentandcontinuesbeyondtheinitial validation batchesforaslongasproductismanufactured marketedSourcesofcriticalvariabilityidentifiedandcontrolledQualitySystemroleinmaintainingvalidatedstate qualitybuiltin nottestedintoproduct ProcessValidation FDACompliancePolicyGuide ProcessValidationRequirementsforDrugProductsandActivePharmaceuticalIngredientsCPG7132c 08 revisiondate12March2004FDAIndustryGuidelineonProcessValidation currentlybeingrevised SystemInspections QualityFacilitiesandEquipmentMaterialsProductionPackaging LabelingLaboratoryControls MostCommonGMPDeficienciesbySystem API DosageInspectionsfor2004 5 StateofControl Detailedinspectionofasystemsothatthefindingsreflectthestateofcontrolinthatsystemforeveryproduct profile classIfoneofthesixsystemsisoutofcontrol thefirmisconsideredoutofcontrolAsystemisconsideredoutofcontrolbasedonGMPdeficiencieswhichsuggestlackofassuranceofquality QualitySystem QualitymustbebuiltintotheprocessQualityisnottestedintotheproductAssuranceofQualitycomesfrom Designofrobustprocessbasedonthoroughknowledgeofthatprocessandthesourcesofvariability EffectiveQualitySysteminplace RoleofManagementinQS Managementisresponsiblefor OrganizationalstructureAllProcessesAllProceduresFacilities ResourcesInshort everythingtoinsureproductquality customersatisfactionandcontinuousimprovement QualitySystemResponsibilities AssuresoverallcompliancewithcGMPsReviewandapprovaldutiesfor ProductQualityReviews atleastannually ComplaintreviewsDiscrepancy failureinvestigationsChangeControlCAPA CorrectiveAndPreventiveAction Qualitysystem continued 6 Reprocess Rework7 Validation Revalidation8 Rejects9 StabilityFailures Outoftrenddata10 Quarantineproducts11 DocumentedGMP JobRelatedTraining LaboratoryControlSystem AdequatelabfacilitiesundertheQualityUnitwhichisindependentfromProductionAdequatelystaffedlaboratories supervisoryandbenchpersonnel Writtenspecificationsforrawmaterials intermediates APIs labels packagingWrittenproceduresforsampling testing approvalorrejectionofmaterialsandfortherecordingandstorageofdataChangecontrolforwrittenproceduresMethodvalidation revalidation LaboratoryControlSystem ReferenceStandards primary secondary EquipmentQualificationCalibration writtenprocedures schedule documentationValidationandSecurityforcomputerizedhandlingoftestresultsandrelateddata systemforassuringintegrityofalllabdataLaboratorycontrolsfollowedanddocumented LaboratoryControlSystem Writtenprocedure SOP coveringoutofspecification oos resultsInvestigationof oos resultsconductedinatimelymannerasperSOPanddocumented completerecordsmaintained Conclusionsfrom oos investigationsdocumentedandcorrectiveactions needforadditioninvestigationidentifiedandimplemented oos reviewincludedinProductQualityReviews LaboratoryControlRecords DescriptionofsamplesIdentificationofmethodusedRawdataforsample standardpreparation reagentsCompleterecordofalldatafromtestingRecordofallcalculationsStatementofthetestresults howcomparewithestablishedacceptancecriteriaSignatureofthepersonwhoperformedeachtest datestestsperformedDate signatureofsecondqualifiedpersonwhoreviewedoriginaltestrecordsforaccuracy completenessandcompliancewithestablishedstandards ProductionSystem Training documented job related MasterproductionandcontrolrecordsBatchproductionandcontrolrecordsChangecontrolprocedureContemporaneous accurateandcompletebatchproductiondocumentationImplementationanddocumentationofin processcontrols tests andexaminations Productionsystem continued Adequatewrittenprocedures practiceforcharge inofmaterialsIdentificationofequipmentwithcontents stageofmanufacturing statusEquipmentcleaningrecordsEstablishedtimelimitsforcompletionofproductionsteps stages Productionsystem continued DeviationsinvestigatedanddocumentedcontemporaneouslywithinvestigationProcessvalidationbasedonknowledgeofprocess scientificbasisforidentifyingcriticalsteps criticalprocessparameters controlpoints Justificationandconsistencyofin processspecificationsandfinalproductspecificationsData informationdocumentedandavailabletoQualityUnitforreview trending investigationsetc Facilities EquipmentSystem FACILITIESLocation design constructionappropriatetofacilitatecleaning maintenance operationsLayoutandairhandlingdesignedandconstructedtopreventcross contaminationFlowofmaterials personneldesignedtopreventmix upsorcontamination Facilities EquipmentSystem Definedareasorothercontrolsystemstopreventmix upsorcontaminationIncomingmaterials id quarantine Samplingarea preventcontamination Quarantine intermediates APIs ReleasedmaterialsRejection Facilities EquipmentSystem EQUIPMENTAppropriatedesign size location non reactiveproductcontactsurfacesIdentificationclearlymarkedQualification DQ IQ OQ PQ CalibrationPreventiveMaintenancescheduleandproceduresCleaningproceduresandvalidationRecordsofuse cleaning maintenance Facilities EquipmentSystem Lubricants heatingfluidsorcoolants notcontact alterproductquality ClosedorcontainedequipmentInspectionpriortouse Separatefacilitiesorcontainmentwhereneeded penicillins highlypotentcompoundsetc Utilities Qualifiedandappropriatelymonitored drawingsshouldbeavailableDesignedandconstructedtopreventcontaminationorcross contaminationRecirculatedairtoproduction sameconcern PermanentlyinstalledpipeworkshouldbeappropriatelyidentifiedDrainsofadequatesizewithairbreak Water ProcesswateratminimummeetingWHOguidelinesforpotablewaterJustifyqualityofwaterusedtoachievestatedAPIqualityandestablishspecificationsWatertreatmentfacilitiesvalidatedAPItobeusedforincorporationintosteriledosageform waterusedinlaterstagesshouldbemonitoredandcontrolledfortotalmicrobialcounts objectionableorganismsandendotoxins MaterialsSystem Writtenproceduresforreceipt identification quarantine storage handling sampling testingandapprovalorrejectionofmaterialsSystemtoevaluatesuppliers criticalmaterials PurchasedagainstagreedspecificationChangecontrolprocessforchangingsuppliersUponreceiptcheckforcorrectlabeling sealsBeforeco minglingbulkmaterial id testAssurancesobtainedfromnon dedicatedtankers MaterialsSystem Identificationonlargestoragecontainersandassociatedmanifolds fillinganddischargelinesCodegiventoreceivedbatches statusidentityAtminimum aspecificidentitytestonincomingbatches COASupplierevaluationshouldincludethreefullytestedbatches onefullytestedbatch yearWrittensamplingplanwithjustificationPreventcontaminationofsampledcontainers MaterialsSystem Storedinmannertopreventdegradation contamination noadverseeffectonqualityDrums bags boxesoffthefloorFirstin firstoutRejectedmaterialsidentifiedandcontrolledunderaquarantinesystemEstablishedre test re evaluationperiods Packaging LabelingSystem Writtenproceduresforreceipt identification quarantine sampling examinationand ortestingPifre used cleaned labelingdefaced Labeling AccesstolabelstoragearealimitedWrittenproceduresforreconciliation investigationifdiscrepancyAllexcesslabelswithbatch destroyedObsoletelabelsdestroyedPrintingdevicescontrolledtoinsureaccuracyoflabel againstbatchrecord Printlabelscheckedagainstmasterandacopyplacedintothebatchrecord Packaging LabelingOperations Documentedprocedurestoassurecorrectpackagingmaterials labelsusedOperationsdesignedtopreventmix upsLabels APIname batch storageconditionsShippedAPI Name addressmanufacturer specialtransportconditions expiry retestdateDocumentedclearancebeforeoperationsPackaged labeledintermediatesorAPIsexaminedaspartofpackaging documented Sealemployedtoassurepackageintegrity APIsareDrugSubstances FDAFood DrugandCosmeticActdefinitionofdrugincludes articlesintendedforuseinthediagnosis cure mitigation treatmentorpreventionofdiseaseinmanorotheranimals nodistinctionbetweenAPIs dosageforms BeforeICHQ7A FDAuseddosagedrugregulationsasguidanceforAPIinspectionStilltrue seenextslide however ICHQ7AprovidesguidanceontheapplicationofthosecGMPstoAPIs FromcurrentFDAComplianceProgram56002forDrugManufacturingInspections ThisisthecomplianceprogramforFDAInvestigators thisrevisionintroducedSystemsInspections ThecGMPregulationsarenotdirectrequirementsformanufactureofAPIs buttheyareguidanceforcGMPinAPImanufacture CurrentFDAComplianceGuideonProcessvalidation FromFDACompliancePolicyGuide ProcessValidationRequirementsforDrugProductsandActivePharmaceuticalIngredientsCPG7132c 08 revisiondate12March2004 ValidationofmanufacturingprocessesisarequirementoftheCurrentGoodManufacturingPractice cGMP regulationsforfinishedpharmaceuticals andisconsideredanenforceableelementofcurrentgoodmanufacturingpracticeforactivepharmaceuticalingredients APIs underthebroaderstatutorycGMPprovisionsoftheFederalFood Drug andCosmeticAct DifferencesAPI DosageForm APIsinvolvepurificationstepsGMPcontrolstighterforlaterAPIstepsAPIimpurityprofileiscriticalfocusandstepswhichproduceorremoveimpuritiesrequiregreatercontrolandvalidationDosageformsdonotinvolvepurification SimilaritiesAPIs DosageForms RequiredemonstratedknowledgeofprocessandapplicationofappropriateGMPcontrolstoassuresafety identity strength qualityandpurity SystemsincontroltobeincomplianceLifeCycleApproachtoValidation beyondtheinitial conformancebatches Similaritiesinclude Processesforspecificproductsvaryincomplexity eitherAPIordosagecaninvolvecomplexorsimpleprocesses In ProcessControlsFinishedProductControlsCriticalSteps CriticalProcessParametersProcessValidationQualityAssuranceforconsumerisbasedonunderstanding ControlofSourcesofProcess ProductVariability MoreSimilarities SciencebasedapproachfortheestablishmentofprocessesKnowledgeofprocessbasedonProcessDevelopmentworkDesignOfExperiments DOE QualitySystem review trending ContinuousImprovementpossiblewithinwellcharacterizedprocess